Silicosis is an occupational disease caused by inhalaling free silicon dioxide (SiO2). Lipid metabolism plays an important role in silicosis. CD36 is a key factor involved in lipid transport, but its mechanism of action in silicosis remains unclear. This study aims to explore the mechanism by which the CD36 inhibitor sulfo-n-succinimide oleate (SSO) targets CD36 to regulate lipid metabolism disorders in silicosis and improve fibrosis. The results showed that SiO2 stimulation led to an increase in CD36 expression, a decrease in LXR and ABCA1 expression, and an increase in lipid dropper formation in rat alveolar macrophages NR8383. The SSO intervention can reverse these changes, resulting in the decrease in CD36 expression, the increase in LXR and ABCA1 expression, the reduction in IL-1β, IL-6 levels and TGF-β1 secretion. Subsequently, after stimulating primary fibroblasts with the supernatants of macrophages in each group, it was found that SSO stimulation reduced the increase of α-SMA and collagen-I induced by SiO2 and improved the level of fibrosis. In addition, in vivo animal experiments have found that SSO intervention alleviated the levels of inflammation, lipid metabolism and fibrosis induced by SiO2 in silicosis mice, and improved the lung function of silicosis mice. These results indicate that SSO regulates SiO2-induced lipid metabolism disorders by targeting CD36, thereby improving SiO2-induced fibrosis. Therefore, SSO targeting CD36 may be a new strategy for treating silica-induced silicosis injury.
Microplastics (MPs) are emerging environmental pollutants, and the gastrointestinal tract represents a major site of exposure following oral intake. This study investigated the effects of polystyrene MP exposure on gut microbiota composition, intestinal barrier integrity, and endotoxin-related inflammatory responses in female rats. MP exposure was associated with compositional alterations in the gut microbiota, including changes in community structure and enrichment of specific bacterial taxa. These microbial changes were accompanied by intestinal mucosal abnormalities, reduced PAS-positive mucin area, decreased expression of the tight junction proteins ZO-1, occludin, and claudin-1, and elevated serum levels of lipopolysaccharide (LPS), interleukin-6 (IL-6), and interleukin-1β (IL-1β). These findings indicate that MP exposure was associated with intestinal barrier impairment and endotoxin-related systemic inflammation. Overall, the present study supports the intestine as a major target of oral MP exposure and suggests that intestinal barrier disruption may contribute to circulating endotoxin accumulation and inflammatory responses. Further studies using direct intestinal permeability assays and targeted mechanistic interventions are needed to clarify the causal relationships among gut microbiota dysbiosis, barrier dysfunction, and systemic inflammation.
In this study, we investigated the effect of the food preservative tert-butylhydroquinone (tBHQ) on the activation of murine CD4+ T cells. We assessed the role of the nuclear factor erythroid 2-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) and conducted protein interaction studies to identify potential molecular targets of tBHQ. BALB/c mice received tBHQ orally (1.5% [w/w]), after which splenic T cells (Th1, Th2, Th17, Treg) were analyzed for number and activation sensitivity. While the number of effector T cells remained unchanged, their response to stimulation was accelerated in tBHQ treated animals. In contrast, Treg cells increased in number after treatment with this food additive but displayed reduction in count upon activation. In vitro experiments showed that tBHQ modulates the differentiation of Th17 and Treg cells. Pretreating these cells with NRF2 inhibitor trigonelline and/or AHR inhibitor TMF (6, 2, 4'-trimetoxi-flavone) altered the effect of tBHQ on these cells. We found 14 candidate targets of this chemical (AHR, KEAP1, NQO1, RORC, TBX21, IL6, GATA3, BCL2, FOXP3, IFNG, JAK2, ALB, TGFBR1, and HSP90AA1). Network analysis revealed coordinated regulation of pathways associated with inflammation, T cell differentiation, and xenobiotic response. In conclusion, our studies highlight the importance of the T cell response after tBHQ exposure and suggest multiple proteins and pathways that are relevant to the immunotoxicity of this compound.
Fluoride and aluminum are two naturally abundant elements with widespread industrial uses. Fluoride is also added to community water supplies as a public health intervention for dental cavity prevention. However, findings from animal studies show potential links of fluoride and aluminum exposure with neurodegenerative disease risk, particularly at high exposure levels. This review uniquely examines neurochemical and neurobiological impacts of fluoride and aluminum exposure as well as whether these processes may increase the risk of common and rare neurodegenerative diseases, including dementia, Parkinson's Disease, and motor neuron disease. Fluoride and aluminum can cross the blood-brain barrier and accumulate in neural tissue, where they can interact to produce neurotoxic effects. Chronic exposure to fluoride and aluminum can cause oxidative stress, mitochondrial dysfunction, brain inflammation, and disruption of essential ions. These effects can contribute to impaired nerve signaling, cell damage, and protein aggregation-key factors in neurodegeneration. Co-exposure to aluminum-fluoride complexes may worsen these effects by increasing amyloid buildup and causing nerve cell death, although more research on aluminum-fluoride interactions is needed. Additionally, many animal studies include relatively high fluoride or aluminum exposure levels, and epidemiological human data are scarce, particularly for less common neurodegenerative diseases. Moreover, these studies often rely on ecological or occupational exposure measures rather than individual biomarkers. Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk, particularly given the mechanistic basis for these potential associations.
Persistent organic pollutants (POPs) such as “dioxins” have been associated with liver disease development. Population studies have highlighted sex-specific susceptibility to POP-induced liver damage, yet toxicological models looking at sex-specific toxic responses and the combined effects of dioxin mixtures remain insufficiently characterized. This study addresses a critical knowledge gap by investigating sex-dependent effects from exposure to a mixture of dioxin and dioxin-like compounds in the context of sex differences and dietary patterns. Male and female C57BL/6 J mice were fed either a low- (LFD) or high-fat diet (HFD) and administered a weekly dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD-10 ng/kg), 3,4,7,8-pentachlorodibenzofuran (PeCDF-80 ng/kg) and polychlorinated biphenyl 126 (PCB126-140 ng/kg) or vehicle control. After 12 weeks, the study was terminated and samples collected for downstream analyses. LFD-fed females exposed to the dioxin mixture displayed reduced liver weight but elevated hepatic triglycerides alongside elevated circulating alanine aminotransferase levels and upregulation of the hepatic fatty acid transport gene Cd36. This observation was absent in diet-matched males. Instead, exposed LFD-fed males showed suppressed de novo lipogenic gene expression coupled with impaired glucose tolerance. Aryl hydrocarbon receptor (AHR) activation (↑Cyp1a1, Cyp1a2) was observed with exposure regardless of sex or diet, although HFD diminished AHR signaling, especially in males. Exposure also resulted in constitutive androstane receptor (CAR) activation (↑Cyp2b10, Cyp2c29), specifically in LFD-fed males. Notably, the dioxin mixture did not exacerbate HFD effects. Sex-specific toxicant responses were observed including dioxin-mediated steatotic liver phenotype in females and glucose perturbation in males, highlighting the negative impact of these chemicals on liver and metabolic outcomes even at low doses.
Environmental lead (Pb) exposure is a risk factor for anxiety and depression. Our previous study showed Pb-induced neurotoxicity involves dysregulated epigenetic modifiers, yet the role of acyl-CoA synthetase short-chain family member 2 (ACSS2)—a key regulator of histone acetylation—in these behaviors remains unclear. Beginning at gestational day 0 (GD 0, plug day) and continuing through weaning (PND 21), C57BL/6 J dams received 100 ppm Pb in drinking water, exposing offspring indirectly via placenta and milk; after weaning, offspring received the same Pb solution directly from drinking water until PND 60. Behavioral tests revealed developmental Pb exposure induced anxiety and depression-like behaviors, accompanied by neuronal morphological damage in the medial prefrontal cortex (mPFC). Mechanistically, Pb inhibited AMP-activated protein kinase (AMPK) activity, suppressing ACSS2 expression and its nuclear translocation, which reduced nuclear acetyl-CoA and histone H3 lysine 9 acetylation (H3K9ac). The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) restored ACSS2 expression and phosphorylation, confirming AMPK as its upstream regulator. These epigenetic changes accompanied downregulated synaptic molecules (GluN2A, VGLUT1, PSD-95). ACSS2 restoration via D-mannose supplementation rescued synaptic protein loss, reversed neuronal structural impairments, and alleviated Pb-induced emotional deficits. Our findings identify the AMPK/ACSS2 pathway as a core regulator of Pb-induced affective disorders, whereby its inhibition epigenetically silences synaptic molecular expression, and nominates ACSS2 augmentation as a viable therapeutic strategy.
The prevalence of antimicrobial resistance and cancer is on the rise, and these ailments create difficulties in therapeutic management and patient compliance. Hence, this necessitates the discovery of novel, less toxic, bioactive compounds from natural sources. This study aimed to investigate the phytochemical composition of leaf extracts from Vachellia karroo, Vachellia kosiensis, Vachellia Farnesiana, Vachellia sieberiana, and Vachellia xanthophloea using Fourier Transform Infrared Spectroscopy (FTIR) and Gas Chromatography-Mass Spectrometry (GC-MS), as well as their cytotoxic activity and antimicrobial properties. Cytotoxicity was assessed in human breast adenocarcinoma (MCF-7) and colorectal carcinoma (HCT116) cell lines, as well as in normal human lung fibroblast cells (MRC5), to determine selectivity. Antimicrobial activity was evaluated against Staphylococcus aureus, Escherichia coli, and Candida albicans. The FTIR analysis indicated the presence of functional groups representing phenols, carboxylic groups, hydroxy groups, alcohols and benzene rings. GC-MS was performed on five species of Vachellia and confirmed 51 volatile compounds, including phytol, germanicol, and supraene. Among all the extracts, V. karroo and V. xanthophloea presented the most cytotoxic activity with IC₅₀ = 9.61 ± 1.00 and 9.82 ± 0.96 μg/mL against the MCF-7 cells and 3.51 ± 1.05 and 10.20 ± 0.96 μg/mL against the HCT116 cells. In addition, all the extracts show lower cytotoxicity to MRC-5 normal cells (IC₅₀ > 20 μg/mL), thus indicating good selectivity with camptothecin used as a positive control. V. karroo showed cytotoxic activity with IC₅₀ values of 9.61 ± 1.00 and 3.51 ± 1.05 μg/mL against MCF-7 and HCT116 cells, while camptothecin exhibited IC₅₀ values of 5.52 ± 0.70, 6.52 ± 0.76 and 4.60 ± 0.56 μg/mL against MRC-5, MCF-7 and HCT116 cells. The extracts showed IC₅₀ values of >20 μg/mL against MRC-5 cells, suggesting non-toxicity. As mentioned earlier, the extracts also showed a great range of antibacterial activity against S. aureus, E. coli and C. albicans. V. karroo showed minimum inhibitory concentrations (MICs) of 1.25, 2.50 and 5.00 mg/mL against S. aureus, E. coli and C. albicans, respectively and V. kosiensis with MIC values of 0.31, 1.25 and > 10.00, respectively. This study revealed the presence of several diverse and significant phytochemicals in the leaves. The bioactivities and low toxicity towards normal cells are indicative of the potential for cancer and associated bacterial co-infection treatment.
Airway epithelial ferroptosis is critically involved in PM2.5-driven asthmatic airway damage, and our previous studies have demonstrated the protective role of club cell protein 16 (CC16) against fine particulate matter (PM2.5)-induced airway inflammation by inhibiting airway epithelial ferroptosis using C57BL/6 J mouse and TC-1 cell model. Nevertheless, it remains unclarified whether CC16 exerts its anti-ferroptotic effects through interacting with E-cadherin, which represents a core research gap absent in our previous studies. Herein, we established PM2.5-intervened asthmatic mice and TC-1 cell models to explore the undiscovered molecular mechanism. Quantitative proteomics combined with bioinformatics screening identified E-cadherin as a pivotal downstream target of CC16. PM2.5 exposure markedly inhibited E-cadherin expression and aggravated epithelial ferroptosis, while CC16 intervention efficiently restored E-cadherin levels, elevated NRF2/GPX4/SLC7A11 expression, suppressed ACSL4, and reduced lipid peroxidation. This study first verified the direct binding interaction between CC16 and E-cadherin via molecular docking, Co-IP and pull-down assays. Furthermore, CDH1 knockdown completely abolished CC16-mediated inhibition of ferroptosis and epithelial injury. Collectively, this work establishes a novel CC16/E-cadherin/ferroptosis signaling axis, demonstrating that E-cadherin is an indispensable mediator for CC16 to relieve PM2.5-triggered airway damage. These findings substantially complement and advance the mechanistic system of CC16-related airway protection, providing novel targets for environmental asthma therapy.
Glycosphingolipids (GSLs) represent an important group of bioactive lipids that serve both as structural components of membranes, and as signaling molecules involved in the regulation of numerous biological processes, such as control of cell growth and cell death. Their significant deregulation in colon cancer cells suggests their potential role in the disease progression. Lactosylceramide (LacCer) is a key intermediate in GSL metabolism and an important precursor of more complex GSLs. Here, we studied the impact of inhibition of LacCer synthesis (using selective targeting of specific LacCer synthases (LCS), B4GALT5 or B4GALT6, via CRISPR/Cas9-mediated gene knockdown) on control of the human DLD-1 colon adenocarcinoma cell proliferation, death and chemosensitivity. The downregulation of the selected enzymes, as verified by a decrease in respective mRNA and protein levels, significantly reduced levels of LacCers and several more complex GSLs (in particular, GM3 and GM1a gangliosides) in LCS-knockdown cells. Importantly, it enhanced the sensitivity of DLD-1 cells to the cytotoxic effects of oxaliplatin, a chemotherapy drug commonly used in colorectal cancer treatment. This was demonstrated by a general decrease in cell viability, an enhanced apoptotic cell death, caspase-8,-9,-3 cleavage/activation and cleavage of caspase substrates. We also observed a modulation of endoplasmic reticulum stress response, in particular decreased levels of ATF6, in LCS-knockdown cells treated with oxaliplatin. The present findings support the functional role of LCS in regulating the chemosensitivity of colon cancer cells towards the action of chemotherapy drugs, such as oxaliplatin, with possible further implications for the mechanisms underlying toxic action of platinum-based drugs in cancer cells.
Oral nicotine products are a category of novel tobacco products that deliver nicotine through oral consumption. With increasing tobacco control measures worldwide and growing public health awareness, its safety risk has gained attention. However, the regulatory authorities still lack long-term data for oral nicotine products and limited data on additives, so the continued in-depth research is required in the future. By integrating data from chemical analyses, animal/cell studies, and human cohorts, this review first introduces the main commercially available oral nicotine products and their classifications, analyzes the potentially harmful substances and their concentrations, and then systematically elucidates the health effects of oral nicotine products (including on oral and cardiovascular systems) and their underlying mechanisms. Finally, based on relevant research, it proposes future directions for safety risk studies on oral nicotine products. In summary, this review offers consumers a clearer understanding of the safety risks of oral nicotine products, provides evidence to support their rational use, and delivers insights for companies and regulators to develop effective policies and reduce health risks.
Vinclozolin is a dicarboximide anti-androgenic fungicide that has endocrine-disrupting impact on mammals. Endocrine disruptors are reported to impair mitochondrial function and reduce adenosine triphosphate (ATP) production. Moreover, increasing evidence has linked exposure to endocrine disruptors with metabolic diseases. However, the toxicity of direct exposure to vinclozolin on mitochondrial function remains insufficiently explored. In this study, mitochondria were isolated from mouse liver-one of the primary organs involved in the uptake and processing of toxicants-and directly exposed to vinclozolin. Several markers, including citrate synthase, mitochondrial complex IV (CIV) activity, ATP production, reactive oxygen species/reactive nitrogen species (ROS/RNS) levels, cytochrome c release, glutathione (GSH) levels, and superoxide dismutase (SOD) activity were measured. The results indicated that vinclozolin decreased citrate synthase activity in both sexes and significantly reduced CIV activity only in males. ATP levels showed a decreasing tendency, while ROS/RNS levels showed an increasing tendency particularly in males, without statistical significance. Notably, SOD activity exhibited a sex-dependent increase specifically in females, whereas vinclozolin exposure did not significantly alter GSH levels in either sex. Despite this, basal GSH levels remained significantly higher in females than in males. In both sexes, an increase in cytochrome c release was observed. Collectively, direct mitochondrial exposure to vinclozolin induced dysfunction by impairing energy production, a process mediated by sex-specific antioxidant responses.
Calcium stearyl lactylate (CSL) is a widely used food emulsifier, particularly in pasta products. In this study, we investigated the potential toxicological effects of CSL exposure on organ health and gut microbiota in mice. Over a 12-week period, mice were administered CSL at 50, 500, and 5000 mg/kg·bw. Our study found that CSL exposure induced liver and colon inflammation, significantly elevating hepatic injury markers (ALT and AST). In parallel, key intestinal functional markers (CXCL-1, CXCL-2, IL-1β, TNF-α, ZO-1, and Occludin) were markedly altered, indicating compromised gut barrier integrity. 16S rRNA sequencing revealed that CSL administration disrupted gut microbial diversity, characterized by decreased beneficial bacteria (e.g., Bifidobacterium and Lactobacillus) and increased potentially harmful genera, including Anaerotruncus, Desulfovibrio, and Helicobacter. These findings indicate that long-term CSL intake can induce hepatointestinal damage and provoke significant dysbiosis of the gut microbiome.
In this study, the delivery of three substances (nicotine, propylene glycol (PG), and vegetable glycerin (VG)) in vapor generated by HTPs was evaluated based on the habits and preferences of users. To achieve this, the following five key characteristics were considered: operation method, device temperature, impact of the cartridge, flavor, and capsule break. These key features, influenced by the habits and preferences of users, were shown to affect emission profiles. This study was conducted in compliance with Health Canada Intense and used a smoking machine to capture vapor from HTPs. Each device has different operation methods that can be chosen by users. The cartridge had the most significant impact on substance delivery depending on the operation mechanism. Additionally, device temperature was correlated with concentrations of emitted substances. Tobacco sticks also showed significant impact on substance delivery. Notably, capsule break increased relative standard deviation (RSD) of PG from 2.17% to 10.22% and RSD of VG from 3.57% to 28.07% in Glo Hyper X2 fruitflavored tobacco sticks. These findings suggest that delivery of substances is influenced by conditions of HTPs and the conditions are influenced by the habits, behaviors, and preferences of users.
Nephrotoxicity is a common side effect of cisplatin (CSP), a widely-used anti-tumor chemotherapy drug. Acute kidney injury (AKI) induced by it is characterized by inflammation, apoptosis, and metabolic reprogramming in proximal tubule (PT) cells. However, the key pathways and upstream transcriptional regulators orchestrating these pathological changes remain poorly understood. This study aimed to identify crucial transcription factors (TFs) involved in CSP-induced AKI and to explore potential therapeutic agents targeting them. An integrative multi-omics analysis of public bulk RNA-seq, proteomic, and single-cell RNA-seq datasets was performed to identify dysregulated pathways and key TFs. The expression of Krüppel-like factor 15 (KLF15), the lead candidate TF, was validated in a CSP-induced AKI mouse model (20 mg/kg intraperitoneal injection for 72 h) using RT-qPCR and Western blot. Molecular docking utilizing AutodockVina was employed to virtually screen an FDA-approved drug library for potential compounds targeting KLF15.Transcriptomics and proteomics analyses consistently identified KLF15 as a top-ranked, downregulated TF in CSP induced AKI. Single-cell analysis revealed that PT cells were the most affected, and the loss of Klf15 expression in these cells was strongly associated with a proinflammatory, pro-apoptotic state and suppressed metabolic pathways, including the TCA cycle and fatty acid oxidation. In a murine model of CSP-induced AKI, Klf15 mRNA and KLF15 protein levels were markedly reduced. Furthermore, virtual screening identified 6 drugs, including Simeprevir, Lomitapide, and Avodart, as potential high-affinity compounds targeting human KLF15. In conclusion, our study indicates that the downregulation of KLF15 is a prominent molecular feature in CSP-induced AKI, associated with metabolic failure and injury in proximal tubules.
Flavor additives can contribute to the biological effects of electronic cigarette (e-cigarette) aerosols, yet the mechanisms underlying flavor-related vascular toxicity remain poorly understood. We previously showed that exposure of human aortic smooth muscle cells (AoSMCs) to cinnamon-flavored e-cigarette aerosol induced a marked pro-inflammatory response that was amplified by heating. The present study aimed to identify thermal degradation products derived from cinnamon flavoring that may contribute to this effect. Aerosol condensates were generated from cinnamon-flavored e-liquids under controlled vaping conditions, and a chemical screening approach was used to identify degradation products. Benzaldehyde and phenylacetaldehyde were detected as specific to the heated cinnamon condensate and were subsequently selected for targeted in vitro testing. AoSMCs were exposed to aerosols, unheated e-liquids, or e-liquids supplemented with aldehydes (alone or in combination), and cytotoxicity and pro-inflammatory responses were assessed. Exposure to cinnamon aerosol induced a significant increase in IL-8 release without detectable cytotoxicity. Supplementation of e-liquids with benzaldehyde reproduced much of the IL-8 response observed with the aerosol, whereas phenylacetaldehyde alone elicited only a limited effect. Co-exposure to both aldehydes did not further enhance IL-8 production beyond that induced by benzaldehyde alone, suggesting potential interaction effects among cinnamon-derived degradation products.Taken together, these findings indicate that thermal processing of cinnamon-flavored e-liquids generates aromatic aldehydes that contribute to pro-inflammatory signaling in human vascular smooth muscle cells, with benzaldehyde emerging as a major contributor under the present experimental conditions. This study highlights the importance of considering flavor-derived degradation products when evaluating the vascular toxicity of e-cigarette emissions.
Background:Due to its ability to inhibit the growth of hepatoma cells, brefeldin A (BFA) has been considered a promising drug candidate for liver cancer. However, there is limited research on its safety profile and potential impacts when administered alone or in combination with other anticancer drugs. Objective:To evaluate the safety of BFA in combination with tunicamycin (TM, a candidate anticancer drug) in human normal liver cells (HL-7702) in terms of its ability to induce endoplasmic reticulum (ER) stress and apoptosis. Methods:HL-7702 cells were exposed to BFA (0-2.5 mg/L) and TM (0-5 mg/L), either alone or in combination, for 24 h. Cell viability was measured using the CCK-8 assay, and apoptotic rates were determined using flow cytometry. The mRNA and protein levels of key factors related to cell proliferation, ER stress, and apoptosis were determined using quantitative RT-PCR and Western blot, respectively. Results:BFA and TM, either alone or in combination, significantly reduced the viability of HL-7702 cells. BFA alone and BFA + TM combination could weakly induce apoptosis, increase the expression of caspase 12, and reduce the protein level of proliferating cell nuclear antigen (PCNA). BFA alone and BFA + TM combination could significantly increase the mRNA and protein levels of binding immunoglobulin protein (BiP) and activating transcription factor 4 (ATF4), but did not affect the mRNA and protein levels of C/EBP homologous protein (CHOP) and poly (ADP-ribose) polymerase-1 (PARP-1). Conclusion:This study demonstrates that BFA, alone and in combination with TM, exerts mild pro-apoptotic effects on HL-7702 cells, independent of the CHOP and caspase-3 pathways. These findings underscore the necessity of evaluating the potential hepatotoxicity of BFA-based therapies, particularly in combination treatments, to ensure their safe clinical application.
PM2.5 contributes to lung injury by inducing oxidative stress, inflammatory responses, and apoptosis. Calcitriol exerts a protective role against lung injury by regulating the vitamin D receptor (VDR) and Nrf2 signaling pathways, mitigating PM2.5-induced oxidative stress and inflammation. In this study, we investigated the protective effects of calcitriol against PM2.5-induced apoptosis, oxidative damage, and inflammation in human bronchial epithelial BEAS-2B cells, with a specific focus on the crosstalk between VDR and Nrf2 signaling. BEAS-2B cells were pre-treated with calcitriol (1, 10, 100 nM) for 24 h before PM2.5 exposure (100 µg/mL). Apoptosis, DNA damage, and inflammation were assessed by flow cytometry, ELISA, qRT-PCR, and Western blot analysis. Chromatin immunoprecipitation (ChIP) was performed to evaluate VDR-antioxidant response element (ARE) binding. Calcitriol suppressed apoptotic signaling by reducing p53 phosphorylation and downregulating the mRNA expression of p53 and caspase-3, while also mitigating oxidative DNA damage, as indicated by decreased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in BEAS-2B cells. Additionally, calcitriol suppressed inflammatory responses by downregulating NF-κB activity and the mRNA expression of NF-κB p65 and its downstream pro-inflammatory genes, including IκB-α, TNF-α, and IL-6. Moreover, calcitriol treatment increased VDR protein expression and enhanced Nrf2 activity. ChIP assays demonstrated that calcitriol enhanced VDR binding to AREs, thereby promoting the transcription of key Nrf2-regulated cytoprotective genes, including heme oxygenase-1 (HO-1) and NADPH quinone dehydrogenase 1 (NQO1). These findings provide mechanistic insight into the pharmacological effects of calcitriol, underscoring its potential to alleviate PM2.5-induced cellular injury through VDR-mediated activation of Nrf2 redox signaling.
Diisononyl phthalate (DINP) is a high molecular weight phthalate used in commercial products and polyvinyl chloride production. Herein, a systematic evaluation of DINP evidence streams (i.e., human cancer, animal cancer, and mechanistic data) was carried out to inform carcinogenic hazard in humans. Relevant data from peer-reviewed literature and publicly available laboratory reports were extracted and critically appraised. Mechanistic data were organized according to the Key Characteristics of Carcinogens (KCCs) and integrated into key events in rodent cancer modes of action (MoAs). Evidence from epidemiological studies is limited, but does not indicate an association between DINP exposure and cancer, with three studies reporting no association with breast cancer, and one reporting an imprecise increase in prostate cancer risk. Four chronic bioassays demonstrated DINP causes cancer in rodents, with increases in liver tumors in mice and rats, kidney tumors in male F344 rats, and mononuclear cell leukemia (MNCL) in F344 rats. Mechanistic data strongly support that DINP is non-genotoxic (KCC2), and that in rodents DINP induces oxidative stress (KCC5) and alters cell proliferation (KCC10). Multiple evidence stream integration and interpretation support that DINP elicits rodent-specific liver tumors through the peroxisome proliferator-activated receptor alpha, a MoA widely considered to lack human relevance. Likewise, the weak kidney tumor response in male rats was attributed to α2u-globulin nephropathy, a male rat-specific response. MNCL, a common lesion in aging F344 rats, was not considered relevant for predicting human cancer. Together, these data indicate that DINP is unlikely to pose a carcinogenic hazard to humans.
Microplastic (MP) pollution poses an increasing threat to the aquatic ecosystems, yet most existing detection methods remain largely destructive and spatially limited. Here, we present a novel, non-invasive imaging framework integrated with micro-computed tomography (µ-CT) and fluorescence microscopy to investigate ingestion, accumulation and internal distribution of fluorescently labelled polystyrene microplastics (PS-MP) in the commercially important fish species Labeo rohita. Fluorescence microscopy confirmed presence of MPs in the gastrointestinal (GI) tract, gills, muscle tissues and excreta of exposed fish, whereas, micro-computed tomography (µ-CT) facilitated non-destructive, three-dimensional whole-body imaging, allowing precise localization and visualization of internalized particles within intact organisms. A clear, progressive and exposure-dependent increase in microplastic presence was observed over the 28-day experimental period, supported by non-parametric trend and effect-size analyses, with consistently higher relative burdens under waterborne exposure compared to the dietary exposure, as revealed by complementary µ-CT and fluorescence imaging. Detection of microplastics in muscle tissue indicates systemic translocation beyond primary uptake organs, whereas their presence in excreta confirms active elimination processes. Strong spatial concordance between µ-CT and fluorescence microscopy validates the robustness of the dual-imaging approach. Collectively, this study advances microplastic ecotoxicology by establishing a scalable, high-resolution, non-invasive imaging framework for mapping and tracking microplastic fate in freshwater systems as well as organ-specific microplastic distribution and burden in freshwater fish under environmentally realistic exposure conditions.
As the cosmetic industry replaces traditional animal safety studies with next generation risk assessment approaches, the approach to safety substantiation for peptides used in cosmetic products must also evolve. While the need to provide assurances of safety for local and systemic toxicity endpoints remains the same, adoption of bioinformatic tools developed in the food, agricultural biotechnology, and drug development industries may add to the weight of evidence for the safety substantiation of peptides in cosmetics. Here we review the historical development and safety evaluation of peptides utilized in the cosmetic industry and provide a new safety evaluation framework that incorporates six bioinformatic tools. To test the framework, a variety of peptides (palmitoyl hexapeptide-12, caffeoyl hexapeptide-9, palmitoyl pentapeptide-4, amanitin alpha, conotoxin ArlB, bradykinin, and enkephaline) are evaluated with NCBI BLASTp, ToxinPred3.0, Peptipedia, BIOPEP-UWM, AllerCatPro 2.0, and IEDB bioinformatic tools. The results correctly identified safety concerns (toxins) for amanitin and conotoxin peptides and the biological actions of bradykinin and enkephaline, while palmitoyl hexapeptide-12, caffeoyl hexapeptide-9, and palmitoyl pentapeptide-4 demonstrated sequence homology with extracellular matrix proteins in the skin (collagen, elastin, fibronectin) without the safety concerns of the other peptides. The incorporation of bioinformatic tools into the safety framework provides an additional means to screen for toxins and allergens as well as insights into potential biological activities when sequence homology with existing proteins and peptides occurs. Further testing of the framework by the cosmetic industry is needed to lend support and reveal opportunities for refinements that advance the safety substantiation of peptides.
